Journal article
Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes
Journal of the American Society of Nephrology, Vol.28(1), pp.140-151
01/2017
DOI: 10.1681/ASN.2015080888
PMCID: PMC5198269
PMID: 27151926
Abstract
Klotho is a type-1 membrane protein predominantly produced in the kidney, the extracellular domain of which is secreted into the systemic circulation. Membranous and secreted Klotho protect organs, including the kidney, but whether and how Klotho directly protects the glomerular filter is unknown. Here, we report that secreted Klotho suppressed transient receptor potential channel 6 (TRPC6)-mediated Ca
influx in cultured mouse podocytes by inhibiting phosphoinositide 3-kinase-dependent exocytosis of the channel. Furthermore, soluble Klotho reduced ATP-stimulated actin cytoskeletal remodeling and transepithelial albumin leakage in these cells. Overexpression of TRPC6 by gene delivery in mice induced albuminuria, and exogenous administration of Klotho ameliorated the albuminuria. Notably, immunofluorescence and in situ hybridization revealed Klotho expression in podocytes of mouse and human kidney. Heterozygous Klotho-deficient CKD mice had aggravated albuminuria compared with that in wild-type CKD mice with a similar degree of hypertension and reduced clearance function. Finally, disrupting the integrity of glomerular filter by saline infusion-mediated extracellular fluid volume expansion increased urinary Klotho excretion. These results reveal a potential novel function of Klotho in protecting the glomerular filter, and may offer a new therapeutic strategy for treatment of proteinuria.
Details
- Title: Subtitle
- Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes
- Creators
- Ji-Hee Kim - Departments of Physiology and Global Medical ScienceJian Xie - Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasKyu-Hee Hwang - Departments of Physiology and Global Medical ScienceYueh-Lin Wu - Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; andNoelynn Oliver - Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, ConnecticutMinseob Eom - Department of Pathology, andKyu-Sang Park - Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of KoreaNestor Barrezueta - Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, ConnecticutIn-Deok Kong - Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of KoreaR Paul Fracasso - Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, ConnecticutChou-Long Huang - Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Chou-Long.Huang@UTSouthwestern.edu skcha@yonsei.ac.krSeung-Kuy Cha - Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, Vol.28(1), pp.140-151
- DOI
- 10.1681/ASN.2015080888
- PMID
- 27151926
- PMCID
- PMC5198269
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Grant note
- P30 DK079328 / NIDDK NIH HHS R01 DK085726 / NIDDK NIH HHS R01 DK100605 / NIDDK NIH HHS R01 DK109887 / NIDDK NIH HHS
- Language
- English
- Date published
- 01/2017
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094396402771
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